Submissions for variant NM_000268.4(NF2):c.1385G>A (p.Arg462His)

gnomAD frequency: 0.00011  dbSNP: rs373650983

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229162	SCV000284544	uncertain significance	Neurofibromatosis, type 2	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 462 of the NF2 protein (p.Arg462His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 237618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001011276	SCV001171577	likely benign	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001562976	SCV001785834	likely benign	not provided	2021-01-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31712784)
Genome-Nilou Lab	RCV000229162	SCV002045407	likely benign	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000229162	SCV004821544	uncertain significance	Neurofibromatosis, type 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 462 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with craniopharyngioma who also has a deleterious CTNNB1 missense variant, p.Gly34Glu (PMID: 31712784). This variant has been identified in 8/216786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.